Bortezomib

Hematologic toxicity, including grade 3 and 4 neutropenia and thrombocytopenia may occur; risk is increased in patients with pretreatment platelet counts 3. Monitor frequently throughout treatment; may require treatment interruption, or dosage reduction. Management with platelet transfusions, supportive care, and/or myeloid growth factors may be necessary. Nadirs generally occur following the last dose of a cycle and recover prior to the next cycle. Hemorrhage (gastrointestinal and intracerebral) due to low platelet count has been observed. Neutropenic fever has been observed.

Acute development or exacerbation of HF and new onset decreased left ventricular ejection fraction (LVEF) have been reported with bortezomib; some cases have occurred in patients without risk factors for HF and/or decreased LVEF. Monitor closely in patients with risk factors for HF or existing heart disease. Isolated case of QTc prolongation have been reported with bortezomib.

Nausea, vomiting, diarrhea, or constipation may occur; may require antiemetics or antidiarrheals. Ileus may occur. Administer fluid and electrolytes to prevent dehydration; interrupt therapy for severe symptoms.

Acute liver failure has been reported (rarely) in patients receiving multiple concomitant medications and with serious underlying conditions. Hepatitis, transaminase increases, and hyperbilirubinemia have also been reported; interrupt therapy to assess reversibility. Use caution in patients with hepatic dysfunction; reduced initial doses are recommended for moderate and severe hepatic impairment (exposure is increased); closely monitor for toxicities. Limited data exists for patients that have been rechallenged.

Herpes (zoster and simplex) reactivation has been reported with bortezomib; consider antiviral prophylaxis during therapy.

Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, and laryngeal edema have been reported with bortezomib.

Bortezomib may cause hypotension (including postural and orthostatic); use caution with dehydration, history of syncope, or medications associated with hypotension (may require adjustment of antihypertensive medication, hydration, and mineralocorticoids and/or sympathomimetics).

Bortezomib may cause or worsen peripheral neuropathy (usually sensory but may be mixed sensorimotor); risk may be increased with previous use of neurotoxic agents or preexisting peripheral neuropathy (in patients with preexisting neuropathy, use only after risk versus benefit assessment); monitor for signs and symptoms; adjustment of dose and/or schedule may be required. The incidence of grades 2 and 3 peripheral neuropathy may be lower with SubQ route (compared to IV); consider SubQ administration in patients with preexisting or at high risk for peripheral neuropathy. The majority of patients with ≥ grade 2 peripheral neuropathy have improvement in or resolution of symptoms with dose adjustments or discontinuation. In a study of elderly patients receiving a weekly bortezomib schedule with combination chemotherapy, the incidence of peripheral neuropathy was significantly reduced without an effect on outcome (Boccadoro 2010; Palumbo 2009). The generic product (by Fresenius Kabi) is NOT approved for subcutaneous administration.

Posterior reversible leukoencephalopathy syndrome (PRES, formerly RPLS) has been reported (rarely). Symptoms of PRES include confusion, headache, hypertension, lethargy, seizure, blindness and/or other vision, or neurologic disturbances; discontinue bortezomib if PRES occurs. MRI is recommended to confirm PRES diagnosis. The safety of reinitiating bortezomib in patients previously experiencing PRES is unknown.

Progressive multifocal leukoencephalopathy (PML) has been rarely observed; evaluate promptly any new onset or worsening neurologic symptoms (eg, confusion, loss of balance, vision disturbances, reduced strength or weakness in an arm/leg).

Pulmonary disorders (some fatal) including pneumonitis, interstitial pneumonia, lung infiltrates, and acute respiratory distress syndrome (ARDS) have been reported. Pulmonary hypertension (without left heart failure or significant pulmonary disease) has been reported rarely. Promptly evaluate with new or worsening cardiopulmonary symptoms; therapy interruption may be required.

Tumor lysis syndrome has been reported with bortezomib; risk is increased in patients with high tumor burden prior to treatment; monitor closely. Disease-related concerns:

Hyper- and hypoglycemia may occur in diabetic patients receiving oral hypoglycemics; monitor; may require adjustment of diabetes medications. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Coadministration of strong CYP3A4 inhibitors may increase bortezomib exposure; monitor for toxicity and consider dose reduction if concurrent therapy cannot be avoided. Efficacy may be reduced when administered with strong CYP3A4 inducers; concomitant use is not recommended. Other warnings/precautions:

For SubQ (Velcade only) or IV administration only. Intrathecal administration is contraindicated; inadvertent intrathecal administration has resulted in death. Bortezomib should NOT be prepared during the preparation of any intrathecal medications. After preparation, keep bortezomib in a location away from the separate storage location recommended for intrathecal medications. Bortezomib should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration. The reconstituted concentrations for IV and SubQ administration are different; use caution when calculating the volume for each route and dose. The manufacturer provides stickers to facilitate identification of the route for reconstituted vials. The generic product (by Fresenius Kabi) is approved for IV administration only.